This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Stress is believed to be an etiological factor in the abuse of ethanol. However, the role of stress in the risk for excessive ethanol consumption is difficult to untangle from the stress derived from excessively drinking alcohol. A starting point is to operationally define stress as activation of the hypothalamic-pituitary-adrenal (HPA) axis through measurable changes in circulating levels of the hormones adrenocorticotropin (ACTH) from the pituitary and cortisol from the adrenals. Monkeys show clear individual differences in endocrine response of the HPA axis to stressful events and also clear individual differences in the amount of ethanol they choose to self-administer. To address the causal interaction of stress and excessive ethanol interaction, we proposed to characterize individual differences in HPA response to stress prior to, during and following chronic ethanol self administration. Further, the very nature of endocrine response to stress brings into focus the concept of neurocircuitries underlying information flow, integration and functional output. Viewing the HPA response as an intermediate determinant of behavior guides a translational endeavor into the realm of intermediate phenotypes or "endophenotypes". To address the predictive validity of an HPA response as an endophenotype underlying the risk of excessive ethanol self-administration, we have screened a large population of monkeys for specific HPA responses. Individuals on the extreme ends of the population distribution of the potential endophenotype were characterized in the ethanol self-administration procedure. Gene polymorphisms to identify those associated with an HPA response endophenotype are underway.